Abstract

Since its domestication over 100 years ago, the laboratory rat has been the preferred
experimental animal in many areas of biomedical research (Lindsey & Baker 2006). Its
physiology, size, genetics, reproductive cycle, cognitive and behavioural characteristics
have made it a particularly useful animal model for studying many human disorders
and diseases. Indeed, through selective breeding programmes numerous strains have
been derived that are now the mainstay of research on hypertension, obesity and
neurobiology (Okamoto & Aoki 1963; Zucker & Zucker 1961). Despite this wealth of
genetic and phenotypic diversity, the ability to manipulate and interrogate the genetic
basis of existing phenotypes in rat strains and the methodology to generate new rat
models has lagged significantly behind the advances made with its close cousin, the
laboratory mouse. However, recent technical developments in stem cell biology and
genetic engineering have again brought the rat to the forefront of biomedical studies
and enabled researchers to exploit the increasingly accessible wealth of genome
sequence information. In this review we will describe how a breakthrough in
understanding the molecular basis of self-renewal of the pluripotent founder cells of the
mammalian embryo, embryonic stem (ES) cells, enabled the derivation of rat ES cells
and their application in transgenesis. We will also describe the remarkable progress
that has been made in the development of gene editing enzymes that enable the
generation of transgenic rats directly through targeted genetic modifications in the
genomes of zygotes. The simplicity, efficiency and cost-effectiveness of the
CRISPR/Cas gene editing system in particular, means that the ability to engineer the
rat genome is no longer a limiting factor. The selection of suitable targets and gene
modifications will become a priority: a challenge where ES culture and gene editing
technologies can play complementary roles in generating accurate bespoke rat models
for studying biological processes and modelling human disease.